To determine the association between all-cause mortality and dietary protein intake in patients with chronic kidney disease, we performed a large-scale, 8-y prospective cohort study in 98,489 maintenance hemodialysis patients from a multicenter dialysis care provider. Compared with the reference level (60 to <70 g/d), low protein nitrogen appearance (PNA) levels [<30 g/d, HR: 1.40 (95% CI: 1.30, 1.50); 30 to <40 g/d, HR: 1.33 (95% CI: 1.28, 1.39)] was associated with higher all-cause mortality, and high PNA levels [≥110 g/d, HR: 0.92 (95% CI: 0.88, 0.97); 100 to <110 g/d, HR: 0.87 (95% CI: 0.82, 0.91)] were associated with lower all-cause mortality in all analyses. This association was also found in subanalyses performed among racial and hypoalbuminemic groups. Hence, using PNA as a surrogate for protein intake, a low daily dietary protein intake is associated with increased risk of death in all hemodialysis patients. Whether the association between dietary protein intake and survival is causal or a consequence of anorexia secondary to protein-energy-wasting/inflammation or other factors should be explored in interventional trials.

Therapeutic development and monitoring require demonstration of effects on disease phenotype. However, due to the complexity of measuring clinically-relevant effects in rare multisystem diseases, robust biomarkers are essential. For the mucopolysaccharidoses (MPS), the measurement of glycosaminoglycan levels is relevant as glycosaminoglycan accumulation is the primary event that occurs due to reduced lysosomal enzyme activity. Traditional dye-based assays that measure total glycosaminoglycan levels have a high background, due to a normal, baseline glycosaminoglycan content in unaffected individuals. An assay that selectively detects the disease-specific non-reducing ends of heparan sulfate glycosaminoglycans that remain undegraded due to deficiency of a specific enzyme in the catabolic pathway avoids the normal background, increasing sensitivity and specificity. We evaluated glycosaminoglycan content by dye-based and non-reducing end methods using urine, serum, and cerebrospinal fluid from MPS I human samples before and after treatment with intravenous recombinant human alpha-l-iduronidase. We found that both urine total glycosaminoglycans and serum heparan sulfate derived non-reducing end levels were markedly decreased compared to baseline after 26 weeks and 52 weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26 weeks and 81.3% at 52 weeks) compared to urine total glycosaminoglycans (68.3% at 26 weeks and 62.4% at 52 weeks, p < 0.001). Unexpectedly, we also observed a decrease in non-reducing end levels in cerebrospinal fluid in all five subjects for whom samples were collected (mean 41.8% reduction, p = 0.01). The non-reducing ends in cerebrospinal fluid showed a positive correlation with serum non-reducing end levels in the subjects (r² = 0.65, p = 0.005). Results suggest utility of the non-reducing end assay in evaluating a therapeutic response in MPS I.

© 2015 Elsevier Inc. Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8. years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.